The problems of obesity and insulin resistance have been linked to type 2 diabetes. Diabetes is on the rise; fully effective treatments are lacking. In the spectrum from obesity, insulin resistance, to diabetes, profound metabolic dysfunction is linked to increased risk for cardiovascular disease. Our goal is to uncover fundamental mechanisms by which macrophage inflammation impacts metabolic dysfunction in high fat feeding and obesity. Our preliminary data reveal that in high fat feeding in mice, ligands of the receptor for AGE (RAGE) are increased in key metabolic tissues even before the development of frank diabetes. Our data reveal that genetic deletion of RAGE results in significant protection against high fat feeding induced obesity and insulin resistance. Importantly, the accumulation, inflammatory polarization, and metabolic properties of adipose tissue macrophages are greatly reduced by deletion of RAGE. We will address the hypothesis that macrophage RAGE regulates obesity, adiposity and metabolic dysfunction in high fat feeding, both inherently and via cross-talk with the adipocyte. Our Project will explore four key properties of macrophage inflammation to discover RAGE-dependent mechanisms in high fat feeding: monocyte recruitment; macrophage retention and stasis; polarization; and metabolic regulation. Finally, we explore how the binding of the RAGE cytoplasmic domain to the formin, mDia1, which is required for RAGE signaling, contributes to macrophage dysfunction in high fat feeding. Translational studies relevant to human subjects will include examination of human adipose tissue macrophages in obesity and, in preclinical models, the testing of novel small molecule antagonists of RAGE signal transduction.